Jeffery initially accepted an offer from Davis Polk & Wardwell, before moving on to Goldman Sachs in 1983. He became Managing Partner of Goldman Sachs's European Financial Institutions Group in London in 1992, and then Managing Partner of the Goldman Sachs Paris office in 1997.

Currently Reuben Jeffery III serves as senior advisor at CSIS (Center for Strategic and International Studies). On July 27, 2010, Jeffery was hired to be CEO of Rockefeller & Co., a NYC-based asset manager with $43 billion under management.

On May 8, 2012, Jeffery was reported donating $32,000 to Romney Victory Inc.

In 2013, Jeffery was a signatory to an amicus curiae brief submitted to the Supreme Court in support of same-sex marriage during the Hollingsworth v. Perry case.[4]